Process for producing optically active azetidine-2-carboxylic acid

ABSTRACT

The present invention provides a process for preparing optically active azetidine-2-carboxylic acids using readily available reagents of relatively low price in the industry. Thus, there is provided optically active azetidine-2-carboxylic acid, and a process for producing the same by subjecting optically active N-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula (1): ##STR1## to hydrogenolysis in the presence of a catalyst.

This application is a divisional of application Ser. No. 08/924,320,filed on Sep. 5, 1997, now U.S. Pat. No. 5,880,291, the entire contentsof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a process for producing opticallyactive azetidine-2-carboxylic acid and an intermediate for producing thesame.

The optically active azetidine-2-carboxylic acid has been known as anintermediate for producing a pharmaceutical such as an antithromboticagent disclosed in EP 542525.

Optically active azetidine-2-carboxylic acid has been produced by aprocess which has the steps of;

a) reacting azetidine-2-carboxylic acid, which is obtained by a processdisclosed in Journal of Heterocyclic Chemistry, 6, 435 (1969), withbenzyloxycarbonyl chloride to giveN-(benzyloxycarbonyl)-azetidine-2-carboxylic acid,

b) subjecting N-(benzyloxycarbonyl)-azetidine-2-carboxylic acid tooptical resolution using an optically active tyrosine hydrazide, andthen

c) subjecting the obtained optically activeN-(benzyloxycarbonyl)-azetidine-2-carboxylic acid to hydrogenolysis togive an optically active azetidine-2-carboxylic acid [Journal ofHeterocyclic Chemistry, 6, 993 (1969)].

The prior art method for preparing optically activeazetidine-2-carboxylic acid, however, had difficulties in that itrequires, as a reagent for optical resolution, an optically activetyrosine hydrazide which is expensive and not readily available on theindustrial scale.

As a result of extensive research, the present inventors have foundoptically active N-(alkylbenzyl)azetidine-2-carboxylic acid which can bereadily converted to the desired optically active azetidine-2-carboxylicacid by a hydrogenolysis reaction; and

a process for producing optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid or an ester thereof throughan efficient optical resolution using readily available dicarboxylicacid, whereby completing the present invention.

Thus, the present invention provides:

1. optically active N-(alkylbenzyl)azetidine-2-carboxylic acidrepresented by the formula (1): ##STR2## wherein R¹ is an alkyl grouphaving 1 to 6 carbon atoms, X is a phenyl group which may be substitutedwith at least one group selected from a halogen atom, a hydroxyl group,an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1to 6 carbon atoms; and

a and b independently designate asymmetric carbon atoms;

2. a process for producing optically active azetidine-2-carboxylic acid,which comprises: subjecting the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1) as defined above to hydrogenolysis in the presence of a catalyst.

3. a process for producing optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1) as defined above, which comprises hydrolyzing optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2): ##STR3## wherein R² is an aryl group or a saturatedhydrocarbon group which may be substituted with an aryl group and X, R¹,a and b have the same meaning as defined above, in the presence of anacid or a base.

4. a process for producing optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2) as defined above, which comprises the steps of:

(a) contacting N-(alkylbenzyl)azetidine-2-carboxylic acid esterrepresented by the formula (2)': ##STR4## wherein R¹, R², X and a havethe same meaning as defined above, with a dicarboxylic acid of theformula (5): ##STR5## wherein B is a single bond, a phenylene group, astraight or branched chain alkylene group which may be substituted witha phenyl group, a hydroxy group which may be protected or a halogenatom,

a cyclic alkylene group which may be substituted with a hydroxy groupwhich may be protected, a halogen atom or a phenyl group, or

a straight or branched chain alkenylene group which may be substitutedwith a phenyl group, to obtain an adduct of the formula (6): ##STR6##wherein R¹, R², X, B and a have the same meaning as defined above,

(b) isolating dicarboxylic acid salt of optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (7): ##STR7## wherein X, B, R¹, R², a and b have the samemeaning as defined above, and

(c) treating the obtained salt of the formula (7) with a base.

5. a process for producing optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2) as defined above, which comprises the steps of:

(a) contacting N-(alkylbenzyl)azetidine-2-carboxylic acid esterrepresented by the formula (2)': ##STR8## wherein R¹, R², X and a havethe same meaning as defined above, with a chiral dicarboxylic acid,

(b) isolating diastereomer salt comprising the chiral dicarboxylic acidand optically active N-(alkylbenzyl)azetidine-2-carboxylic acid esterrepresented by the formula (2) as defined above, and

(c) treating the obtained diastereomer salt with a base.

First a description will be made to the first aspect of the presentinvention, which relates to optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1) as defined above.

In the optically active N-(alkylbenzyl)azetidine-2-carboxylic acidrepresented by the formula (1), examples of the alkyl group representedby the substituent R¹ include a methyl group, an ethyl group, a propylgroup, an isopropyl group, a butyl group, a tert-butyl group and thelike.

X is a phenyl group which may be substituted with at least one groupselected from a halogen atom, a hydroxyl group, an alkyl group having 1to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms.

Examples of the alkyl group include a methyl group, an ethyl group, apropyl group, an isopropyl group, a butyl group, a tert-butyl group andthe like.

Examples of the halogen atom include a chlorine atom, a bromine atom, aniodine atom and a fluorine atom.

Examples of the alkoxy group include a methoxy group, an ethoxy groupand the like, respectively.

In formula (1) above and other formulae of (2), (2)', (4), (6) and (7),a and b each independently designate an asymmetric carbon atom having Sor R configuration.

Examples of the optically active N-(alkylbenzyl)azetidine-2-carboxylicacid represented by the formula (1) include optically active isomers of

N-(1-methylbenzyl)azetidine-2-carboxylic acid,

N-(1-phenylpropyl)azetidine-2-carboxylic acid,

N-[1-(p-tolyl)ethyl]azetidine-2-carboxylic acid,

N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylic acid,

N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylic acid,

N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylic acid,

or N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylic acid.

Specific examples are:

N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid,

N-[(S)-methylbenzyl]azetidine-2-(R)-carboxylic acid,

N-[(R)-methylbenzyl]azetidine-2-(R)-carboxylic acid, and

N-[(R)-methylbenzyl]azetidine-2-(S)-carboxylic acid.

According to the present invention, the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1) can readily be converted to an optically activeazetidine-2-carboxylic acid in high yield by hydrogenolysis in thepresence of a catalyst.

Next a description will be made to the process for producing opticallyactive azetidine-2-carboxylic acid, which comprises subjecting thecompound of the formula (1) as defined above to hydrogenolysis in thepresence of a catalyst.

Such a catalyst includes, for example, platinum on carbon, platinumblack, palladium on carbon, palladium hydroxide on carbon, palladiumacetate, palladium chloride, palladium oxide or palladium hydroxide.Palladium hydroxide or Palladium hydroxide on carbon is preferred. Theamount of the catalyst to be used is within a range usually of 0.0001 to0.5 times, by the weight, of the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1).

For the hydrogenolysis reaction, a reducing agent, for example,hydrogen, hydrazine or its salt such as hydrochloride, carbonate, formicacid or its salt such as an ammonium salt and the like can be used.

In the reaction, usually a solvent is used. The solvent includes, forexample, water;

alcohol solvents such as methanol, ethanol, 2-propanol and the like;

ester solvents such as ethyl acetate, methyl acetate, butyl acetate andthe like;

nitrile solvents such as acetonitrile and the like;

aromatic hydrocarbon solvents such as toluene, xylene, benzene and thelike;

aliphatic hydrocarbon solvents such as hexane, heptane and the like;

halogenated hydrocarbon solvents such as dichloromethane,dichloroethane, chloroform, chlorobenzene, o-dichlorobenzene and thelike;

ether solvents such as diethyl ether, tert-butyl methyl ether and thelike; and

amide solvents such as acetamide, N,N-dimethylformamide,N,N-dimethylacetamide and the like.

These solvents can be used independently or as a mixture thereof. Theamount of the solvent to be used is not particularly limited, and areusually used in an amount within a range of 0.5 to 100 times, by weight,of the optically active N-(alkylbenzyl)azetidine-2-carboxylic acidrepresented by the formula (1).

When hydrogen gas is used in the hydrogenolysis reaction, it is usuallyintroduced by bubbling into the reaction mixture of optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1) and the catalyst while stirring the reaction mixture under hydrogenatmosphere at an ordinary or elevated pressure.

When a reducing agent other than hydrogen gas is employed in thehydrogenolysis reaction, the reducing agent is usually added to amixture of optically active N-(alkylbenzyl)azetidine-2-carboxylic acidrepresented by the formula (1) and the catalyst.

In both cases, the reaction temperature is usually within a range of -50to 200° C.

The optically active azetidine-2-carboxylic acid can readily be isolatedfrom the reaction solution after completion of reaction by aconventional method. For example, the catalyst is filtered off and thenthe solvent is evaporated from the filtrate to yield the product. Theproduct may be further purified by recrystallization, columnchromatography or the like, if necessary.

The hydrogenolysis reaction proceeds with retention of configuration atthe asymmetric carbon atom designated by b in the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(1).

The N-(alkylbenzyl)azetidine-2-carboxylic acid represented by theformula (1) can readily be prepared by hydrolyzing optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2): ##STR9## wherein R² is an aryl group or a saturatedhydrocarbon group which may be substituted with an aryl group and X, R¹and a and b have the same meaning as defined above, in the presence ofan acid or a base.

The aryl group represented by R² includes phenyl group or the like; and

the saturated hydrocarbon group which may be substituted with an arylgroup includes an alkyl group having 1 to 10 carbon atoms such as amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an octyl group and the like; and

alicyclic group having 3 to 10 carbon atoms such as a menthyl group, anisomenthyl group, a bornyl group, an isobornyl group and the like.

Said alkyl group may be substituted with an aryl group such as phenylgroup, tolyl group and the like.

Examples of the optically active N-(alkylbenzyl)azetidine-2-carboxylicacid ester represented by the formula (2) include optically activeisomers of:

methyl N-(1-methylbenzyl)azetidine-2-carboxylate,

ethyl N-(1-methylbenzyl)azetidine-2-carboxylate,

butyl N-(1-methylbenzyl)azetidine-2-carboxylate,

octyl N-(1-methylbenzyl)azetidine-2-carboxylate,

isopropyl N-(1-methylbenzyl)azetidine-2-carboxylate,

benzyl N-(1-methylbenzyl)azetidine-2-carboxylate,

methylbenzyl N-(1-methylbenzyl)azetidine-2-carboxylate,

phenethyl N-(1-methylbenzyl)azetidine-2-carboxylate,

phenyl N-(1-methylbenzyl)azetidine-2-carboxylate,

bornyl N-(1-methylbenzyl)azetidine-2-carboxylate,

isobornyl N-(1-methylbenzyl)azetidine-2-carboxylate,

menthyl N-(1-methylbenzyl)azetidine-2-carboxylate,

isomenthyl N-(1-methylbenzyl)azetidine-2-carboxylate,

methyl N-(1-phenylpropyl)azetidine-2-carboxylate,

ethyl N-(1-phenylpropyl)azetidine-2-carboxylate,

butyl N-(1-phenylpropyl)azetidine-2-carboxylate,

octyl N-(1-phenylpropyl)azetidine-2-carboxylate,

isopropyl N-(1-phenylpropyl)azetidine-2-carboxylate,

benzyl N-(1-phenylpropyl)azetidine-2-carboxylate,

methylbenzyl N-(1-phenylpropyl)azetidine-2-carboxylate,

phenethyl N-(1-phenylpropyl)azetidine-2-carboxylate,

phenyl N-(1-phenylpropyl)azetidine-2-carboxylate,

bornyl N-(1-phenylpropyl)azetidine-2-carboxylate,

isobornyl N-(1-phenylpropyl)azetidine-2-carboxylate,

menthyl N-(1-phenylpropyl)azetidine-2-carboxylate,

isomenthyl N-(1-phenylpropyl)azetidine-2-carboxylate,

methyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

ethyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

butyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

octyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

isopropyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

benzyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

methylbenzyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

phenethyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

phenyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

bornyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

isobornyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

menthyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

isomenthyl N-[1-(p-tolyl)ethyl]azetidine-2-carboxylate,

methyl N-[1-(p-chlorophenyl)ethyl ]azetidine-2-carboxylate,

ethyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

butyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

octyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

isopropyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

benzyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

methylbenzyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

phenethyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

phenyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

bornyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

isobornyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

menthyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

isomenthyl N-[1-(p-chlorophenyl)ethyl]azetidine-2-carboxylate,

methyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

ethyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

butyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

octyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

isopropyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

benzyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

methylbenzyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

phenethyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

phenyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

bornyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

isobornyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

menthyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

isomenthyl N-[1-(2,4-dichlorophenyl)ethyl]azetidine-2-carboxylate,

methyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

ethyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

butyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

octyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

isopropyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

benzyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

methylbenzyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

phenethyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

phenyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

bornyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

isobornyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

menthyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

isomenthyl N-[1-(p-methoxyphenyl)ethyl]azetidine-2-carboxylate,

methyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

ethyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

butyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

octyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

isopropyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

benzyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

methylbenzyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

phenethyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

bornyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

bornyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

isobornyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate,

menthyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate, and

isomenthyl N-[1-(4-hyoxyphenyl)ethyl]azetidine-2-carboxylate.

These optically active N-(alkylbenzyl)azetidine-2-carboxylic acid esterrepresented by the formula (2) may be used in the form of salts such ashydrochloride, phosphate or the like.

The acid to be used in the hydrolysis includes, for example, inorganicacids such as hydrochloric acid, sulfuric acid, phosphoric acid and thelike; and

organic acids such as methanesulfonic acid, p-toluenesulfonic acid,acetic acid, 2-ethylhexanoic acid, benzoic acid, trifluoroacetic acidand the like.

The base to be used in the hydrolysis includes, for example, alkalimetal hydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like;

alkaline earth metal hydroxides such as barium hydroxide, calciumhydroxide and the like;

alkali metal carbonates such as sodium carbonate, potassium carbonateand the like;

alkali metal hydrogen carbonates such as sodium hydrogen carbonate,potassium hydrogen carbonate and the like; and

alkoxides such as sodium methoxide, potassium tert-butoxide and thelike.

The acid or base is used in an amount within a range usually of 0.1 to20 moles per mole, preferably of 0.1 to 5 moles per mole of theoptically active N-(alkylbenzyl)azetidine-2-carboxylic acid esterrepresented by the formula (2). Water is usually used in an amountwithin a range or 1 to 100 times, by weight, of the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2).

An organic solvent can be used in the hydrolysis reaction. Said organicsolvent is not particularly limited insofar as it does not adverselyaffect the reaction and includes: for example, alcohol solvents such asmethanol, ethanol, 2-propanol and the like;

nitrile solvents such as acetonitrile and the like;

hydrocarbon solvents such as toluene, benzene, xylene, hexane, heptaneand the like;

halogenated hydrocarbon solvents such as dichloromethane,dichloroethane, chloroform, chlorobenzene, o-dichlorobenzene and thelike;

ether solvents such as diethyl ether, tert-butyl methyl ether and thelike;

amide solvents such as acetamide, N,N-dimethylformamide,N,N-dimethylacetamide and the like;

nitro compound solvents such as nitrobenzene, nitromethane and the like;

sulfoxide solvents such as dimethylsolfoxide and the like.

The reaction is usually carried out by mixing the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2) with an acid or a base in water. The reaction temperature iswithin a range usually of -50 to 200° C., preferably of -20 to 150° C.

The optically active N-(alkylbenzyl)azetidine-2-carboxylic acidrepresented by the formula (1) can be isolated from the reaction mixtureafter hydrolysis reaction by a conventional method, for example,evaporation of the solvent from the reaction mixture, neutralization ofthe reaction mixture, extraction or the like.

For example, a volatile acid such as acetic acid is used for hydrolysis,the desired optically active N-[alkylbenzyl]azetidine-2-carboxylic acidcan be obtained by evaporating acetic acid from the resulting reactionmixture. When a nonvolatile acid or an acid having high boiling pointsuch as 2-ethylhexanoic acid, stearic acid or benzoic acid is used, thedesired acid can be obtained by evaporating aqueous layer separated fromthe reaction mixture after extraction of the reaction mixture with anorganic solvent which are not miscible with water. Alternatively, theN-[alkylbenzyl]azetidine-2-carboxylic acid may be used in the sebsequentprocess without isolating.

When the acid or base used in the hydrolysis reaction forms an insolublesalt with an acid or a base used for neutralization of the reactionmixture, such a insoluble salt can be removed first, and then theresulting solution can be subjected to a usual post treatment.

The hydrolysis reaction proceeds with retention of configuration at theasymmetric carbon atom designated by a or b in the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid represented by the formula(2).

Next a description will be made to the process for producing opticallyactive N-(alkylbenzyl)azetidine-2-carboxylic acid ester represented bythe formula (2) as defined above.

The process comprises the steps of:

(a) contacting the N-(alkylbenzyl)azetidine-2-carboxylic acid esterrepresented by the formula (2)' as defined above with a dicarboxylicacid of the formula (5) as defined above to obtain an adduct of theformula (6) as defined above,

(b) isolating the dicarboxylic acid salt of optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (7) as defined above, and

(c) treating the obtained salt of the formula (7) with a base.

Dicarboxylic acid of the formula (5) will be explained below.

Examples of the straight or branched chain alkylene group represented bythe substituent B include:

alkylene groups having 1 to 8 carbon atoms such as methylene group, anethylene group, a propylene group, a butylene group, a hexylene group,octylene group and the like.

The straight or branched chain alkylene groups may be substituted with:

a hydroxy group which may be protected by a protecting group such as amethyl group, an ethyl group, a tert-butyl group, a benzyl group, ap-methoxybenzyl group, a methoxymethyl group, a benzyloxymethyl group, abenzoyl group, a trimethylsilyl group, a tert-butyldimethylsilyl groupand the like; or

a halogen atom such as a chlorine atom, a bromine atom, an iodine atomand a fluorine atom; or

a phenyl group.

Examples of the alkylene group substituted with a phenyl group include,for example, a 2-phenyl-1,1-ethylene group.

Examples of the cyclic alkylene group include cyclic alkylene grouphaving 3 to 10 carbon atoms such as a2,2-dimethyl-1-methyl-1,3-cyclopentylene group, a 1,1-cyclopropylenegroup, a 1,1-cyclobutylene group, a 1,2-cyclopentylene group, a1,2-cyclohexylene group, a 1,3-cyclohexylene group and the like, andthese may be substituted with:

a hydroxy group which may be protected by a protecting group such as amethyl group, an ethyl group, a tert-butyl group, a benzyl group, ap-methoxybenzyl group, a methoxymethyl group, a benzyloxymethyl group, abenzoyl group, a trimethylsilyl group, a tert-butyldimethylsilyl groupor the like;

a halogen atom such as a chlorine atom, a bromine atom, an iodine atomor a fluorine atom and the like; or

a phenyl group.

Examples of the straight or branched chain alkenylene group includevinylene group, ethynylene group and the like and these may besubstituted with a phenyl group.

Specific examples of the dicarboxylic acid represented by the formula(5) include aromatic or aliphatic dicarboxylic acids such as oxalicacid, malonic acid, succinic acid, glutaric acid, adipic acid, subericacid, sebacic acid, camphoric acid, benzylmalonic acid, fumaric acid,maleic acid, acetylenedicarboxylic acid, phthalic acid, isophthalicacid, terephthalic acid, cyclopropanedicarboxylic acid,cyclobutanedicarboxylic acid, cyclopentanedicarboxylic acid,cyclohexanedicarboxylic acid and the like; oxygen-substituteddicarboxylic acids such as malic acid, dibenzoyltartaric acid, tartaricacid and the like; and halogen-substituted dicarboxylic acids such as2,3-dichlorosuccinic acid, 2,3-dibromosuccinic acid and the like.

In the step (a) above, said dicarboxylic acid of the formula (5) is usedin an amount within a range usually of 0.1 to 10 moles per mole,preferably of 0.1 to 2 moles per mole of theN-(alkylbenzyl)azetidine-2-carboxylic acid esters represented by theformula (2)'.

The step (a) can be carried out in the absence of a solvent. However, asolvent may be added, if necessary. The solvent that can be usedincludes, for example, water;

alcohol solvents such as methanol, ethanol, 2-propanol, butanol,ethyleneglycol and the like;

nitrile solvents such as acetonitrile and the like; hydrocarbon solventssuch as toluene, benzene, xylene, hexane, heptane and the like;

halogenated hydrocarbon solvents such as dichloromethane,dichloroethane, chloroform, chlorobenzene, o-dichlorobenzene and thelike;

ether solvents such as diethyl ether, dipropyl ether, dibutyl ether,tetrahydrofuran, tert-butyl methyl ether and the like;

amide solvents such as acetamide, N,N-dimethylformamide,N,N-dimethylacetamide and the like;

nitro compounds such as nitrobenzene, nitromethane and the like; and

sulfoxides such as dimethylsulfoxide and the like.

These solvents can be used independently or as a mixture thereof. Theamount of the solvent is not particularly limited but preferably such anamount of the solvent which enables good stirring of the mixture of thedicarboxylic acid and the compound of the formula (2)' is used. Suchamount is usually within a range of 0.01 to 100 times, preferably of0.01 to 20 times, by weight, of the N-(alkylbenzyl)azetidine-2-carboxylic acid esters represented by the formula (2)'.

The step (a) is carried out, for example, by contacting thediastereomeric mixture of N-(alkylbenzyl)azetidine-2-carboxylic acidesters with the dicarboxylic acid to obtain a product of the formula (6)under stirring, and in a solvent, if necessary. The mixing is usuallyconducted at a temperature range of -80 to 200° C., preferably of -20 to100° C.

In this process, one of the diastereomers ofN-(alkylbenzyl)azetidine-2-carboxylic acid ester predominantly forms adicarboxylic acid salt of the formula (7) and precipitates. Theprecipitated salt can readily be isolated from the reaction mixtureafter completion of the reaction by a conventional method, such as, forexample, by filtration.

One diastereomer of the N-(alkylbenzyl)azetidine-2-carboxylic acid estermay provide no suitable precipitated salt instantly to isolate dependingon the conditions, for example, the use of an excess amount of thedicarboxylic acid, the solubility of a solvent, when used, or theproperties of the salt to be precipitated. However, in such casesfollowing methods can be applied to isolate the desired singlediastereomer.

The salt of the desired single diastereomer can be crystallized orprecipitated by such a conventional method of cooling the solution,adding seed crystals, vibrating, simply standing, or adding a solventthat has poor solubility to the desired salt. If a solvent is used, itis may be removed by evaporation. Then a suitable solvent that has poorsolubility to -he desired salt may be chosen for recrystallization.

Specific examples of such a solvent include:

an alcohol such as methanol, ethanol, 2-propanol, butanol,ethyleneglycol or the like;

a hydrocarbon such as toluene, benzene, xylene, hexane, heptane or thelike; and

an ether such as diethyl ether, dipropyl ether, dibutyl ether,tetrahydrofuran, tert-butyl methyl ether or the like.

Thus crystallized dicarboxylic acid salt of one diastereomer ofN-(alkylbenzyl)azetidine-2-carboxylic acid ester and can readily beseparated, for example, by filtration and may further be purified by anappropriate means such as recrystallization or the like, if necessary.

In the meantime, the salt of the other diastereomer contained in thefiltrate mother liquor after the filtration can readily be recovered bya conventional method such as evaporation of the solvent, and the saltof the desired diastereomer may be further treated with a base to obtainthe desired diastereomer.

The base to be used in step (c) includes, for example, alkali metalhydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like;

alkaline earth metal hydroxides such as calcium hydroxide and the like;

alkali metal carbonates such as sodium carbonate, potassium carbonateand the like;

alkali metal hydrogen carbonates such as sodium hydrogen carbonate,potassium hydrogen carbonate and the like;

alkaline earth metal hydrogen carbonates such as calcium hydrogencarbonate, phosphates such as disodium hydrogen phosphate, sodiumdihydrogen phosphate, dipotassium hydrogen phosphate, potassiumdihydrogen phosphate and the like; and organic bases such astriethylamine, tributylamine and the like.

The base can be used independently or as a mixture thereof and isusually used in an amount within a range of 0.1 to 10 moles per mole ofthe dicarboxylic acid salts of diastereomer of theN-[alkylbenzyl]azetidine-2-carboxylic acid ester.

After the treatment with the base, the desired optically activeN-[alkylbenzyl]azetidine-2-carboxylic acid ester can readily be obtainedfrom the reaction mixture by a conventional process, for example,extraction or the like.

A description will be made to a process for producingN-(alkylbenzyl)azetidine-2-carboxylic acid ester of the formula (2) asdefined above, which comprises reacting di-substituted butyric acidester represented by the formula (3): ##STR10## wherein Y¹ and Y² arethe same or different and are leaving groups and R² has the same meaningas defied above, with an optically active alkylbenzylamine representedby the formula (4): ##STR11## wherein R¹, X and a have the same meaningas defined above, in the presence of a base.

In the di-substituted butyric acid ester represented by the formula (3),examples of the leaving group represented by the substituents Y¹ and Y²include halogen atoms such as a chlorine atom, a bromine atom and aniodine atom, a mesyloxy group, a tosyloxy group, a benzenesulfonyloxygroup, a nitrobenzenesulaonyloxy group and the like.

Said di-substituted butyric acid ester includes, for example,dihalo-substituted butyric acid esters such as methyl2,4-dichlorobutyrate, ethyl 2,4-dichlorobutyrate, butyl2,4-dichlorobutyrate, octyl 2,4-dichlorobutyrate, isopropyl2,4-dichlorobutyrate, benzyl 2,4-dichlorobutyrate, methylbenzyl2,4-dichlorobutyrate, phenethyl 2,4-dichlorobutyrate, phenyl2,4-dichlorobutyrate, menthyl 2,4-dichlorobutyrate, bornyl2,4-dichlorobutyrate, isobornyl 2,4-dichlorobutyrate, methyl2,4-dibromobutyrate, ethyl 2,4-dibromobutyrate, butyl2,4-dibromobutyrate, octyl 2,4-dibromobutyrate, isopropyl2,4-dibromobutyrate, benzyl 2,4-dibromobutyrate, methylbenzyl2,4-dibromobutyrate, phenethyl 2,4-dibromobutyrate, phenyl2,4-dibromobutyrate, menthyl 2,4-dibromobutyrate, bornyl2,4-dibromobutyrate, isobornyl 2,4-dibromobutyrate, methyl2,4-diiodobutyrate, ethyl 2,4-diiodobutyrate, butyl 2,4-diiodobutyrate,octyl 2,4-diiodobutyrate, isopropyl 2,4-diiodobutyrate, benzyl2,4-diiodobutyrate, methylbenzyl 2,4-diiodobutyrate, phenethyl2,4-diiodobutyrate, phenyl 2,4-diiodobutyrate, menthyl2,4-diiodobutyrate, bornyl 2,4-diiodobutyrate, isobornyl2,4-diiodobutyrate, methyl 2,4-dimesyloxybutyrate, ethyl2,4-dimesyloxybutyrate, butyl 2,4-dimesyloxybutyrate, octyl2,4-dimesyloxybutyrate, isopropyl 2,4-dimesyloxybutyrate, benzyl2,4-dimesyloxybutyrate, methylbenzyl 2,4-dimesyloxybutyrate, phenethyl2,4-dimesyloxybutyrate, phenyl 2,4-dimesyloxybutyrate, methyl2,4-ditosyloxybutyrate, ethyl 2,4-ditosyloxybutyrate, butyl2,4-ditosyloxybutyrate, octyl 2,4-ditosyloxybutyrate, isopropyl2,4-ditosyloxybutyrate, benzyl 2,4-ditosyloxybutyrate, methylbenzyl2,4-ditosyloxybutyrate, phenethyl 2,4-ditosyloxybutyrate, phenyl2,4-ditosyloxybutyrate, methyl 2,4-dibenzenesulfonyloxybutyrate, ethyl2,4-dibenzenesulfonyloxybutyrate, butyl2,4-dibenzenesulfonyloxybutyrate, octyl2,4-dibenzenesulfonyloxybutyrate, isopropyl2,4-dibenzenesulfonyloxybutyrate, benzyl2,4-dibenzenesulfonyloxybutyrate, methylbenzyl2,4-dibenzenesulfonyloxybutyrate, phenethyl2,4-dibenzenesulfonyloxybutyrate,. phenyl2,4-dibenzenesulfonyloxybutyrate, methyl2,4-di(nitrobenzenesulfonyloxy)butyrate, ethyl2,4-di(nitrobenzenesulfonyloxy)butyrate, butyl2,4-di(nitrobenzenesulfonyloxy)butyrate, octyl2,4-di(nitrobenzenesulfonyloxy)butyrate, isopropyl2,4-di(nitrobenzenesulfonyloxy)butyrate, benzyl2,4-di(nitrobenzenesulfonyloxy)butyrate, methylbenzyl2,4-di(nitrobenzenesulfonyloxy)butyrate, phenethyl2,4-di(nitrobenzenesulfonyloxy)butyrate, phenyl2,4-di(nitrobenzenesulfonyloxy)butyrate and the like.

The optically active alkylbenzylamine represented by the formula (4)incudes methylbenzylamine, 1-phenylpropylamine, 1-(p-tolyl)ethylamine,1-(p-chlorophenyl)ethylamine, 1-(2,4-dichlorophenyl)ethylamine,1-(p-methoxyphenyl)ethylamine, 1-(4-hydroxyphenyl)ethylamine and thelike, among which (S)-methylbenzylamine and (R)-methylbenzylamine arepreferred in view of availability.

The reaction of the di-substituted butyric acid ester represented by theformula (3) with the optically active alkylbenzylamine represented bythe formula (4) may be carried out in the presence of a base.

The base include, for example, inorganic base including alkali metalhydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide and the like;

alkaline earth metal hydroxides such as barium hydroxide, calciumhydroxide and the like;

carbonates such as sodium carbonate, potassium carbonate, sodiumhydrogen carbonate, potassium hydrogen carbonate and the like;

organic bases such as triethylamine, pyridine, and the like.

The amount of the base to be used is usually in a range of 0.01 to 20moles per mole, preferably of 0.01 to 5 moles per mole of thedi-substituted butyric acid ester.

Alkylbenzylamine of the formula (4) as such may also be used as a basein this reaction, and the amount of the alkylbenzylamine to be used isusually 2 moles or more per mole of the disubstituted butyric acid esterof the formula (3).

Said reaction is usually carried out in a solvent. The solvent is notparticularly limited insofar as it does not adversely affect thereaction and includes, for example, alcoholic solvents such as methanol,ethanol, 2-propanol and the like;

nitrile solvents such as acetonitrile and the like; hydrocarbon solventssuch as toluene, benzene, xylene, hexane, heptane and the like;

halogenated hydrocarbon solvents such as dichloromethane,dichloroethane, chloroform, chlorobenzene, o-dichlorobenzene and thelike;

ether solvents such as diethyl ether, tert-butyl methyl ether and thelike;

amide solvents such as acetamide, N,N-dimethylformamide,N,N-dimethylacetamide and the like;

nitro compound solvents such as nitrobenzene, nitromethane and the like;and

sulfoxide solvents such as dimethylsolfoxide and the like.

These solvents can be used independently or as a mixture thereof and areused in an amount within a range usually of 1 to 100 times, preferably 1to 20 times, by weight, of the di-substituted butyric acid ester.

Said reaction is usually carried out by mixing the di-substitutedbutyric acid ester with the optically active alkylbenzylamine in asolvent.

The reaction temperature is within a range usually of -50 to 200° C. andpreferably of -20 to 150° C. The optically active alkylbenzylamine isused in an amount within a range usually of 0.5 to 20 moles per mole,preferably of 0.5 to 5 moles per mole of the di-substituted butyric acidester.

The diastereomeric mixture of the optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid esters after completion ofthe reaction, can be isolated from the reaction mixture by aconventional method. For example, the mixture is extracted with ahydrophobic organic solvent and the solvent is evaporated from theresulting organic layer.

The optically active N-(alkylbenzyl)azetidine-2-carboxylic acid estercan be isolated from the diastereomeric mixture by a conventionalprocess. For example, the diastereomeric mixture is applied onto achromatography column, or subjected to recrystallization, or the mixturemay be dissolved in acidic water and the obtained aqueous solution maybe extracted fractionally using hydrophobic solvents such as toluene,diethyl ether, hexane and the like while varying pH of the aqueoussolution.

Preferably, the salt of the optically active azetidine-2-carboxylic acidester with the dicarboxylic acid represented by the formula (7) can beobtained by reacting a compound of the formula (2)": ##STR12## whereinR¹, R² and X have the same meaning as defined above, with the chiraldicarboxylic acid in a manner similar to that described above,separating the desired diastereomer and treating the salt with a base.The chiral dicarboxylic acid to be used in said process includes any oneof the optically active isomers of tartaric acid, dibenzoyltartaricacid, malic acid, camphoric acid or the like.

The compound of the formula (2)" is obtained by reacting thedi-substituted butyric acid ester represented by the above formula (3)with an alkylbenzylamine represented by the formula (4)': ##STR13##wherein R¹ and X have the same meaning as defined above, in a mannersimilar to that described above.

EXAMPLES

The present invention will now be described in more detail by means ofExamples, which should not be construed as a limitation upon the scopeof the present invention.

Example 1

Into a solution of methyl (RS)-2,4-dibromobutyrate (48.53 g) dissolvedin acetonitrile (400 ml) was added dropwise (S)-methylbenzylamine (67.87g) at 50° C. and the mixture was stirred at the same temperature for 4hours. Further, (S)-methylbenzylamine (2.26 g) was added at the sametemperature and then the mixture was stirred at the same temperature for6 hours. The mixture was concentrated under reduced pressure. Theobtained residue was mixed with toluene (300 ml) and concentrated againunder reduced pressure to remove acetonitrile. The obtained residue wascombined with ether (300 ml) and the mixture was stirred for 2 hours.After standing, precipitated solid substance was filtered off and thefiltrate was concentrated to give methylN-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylate (59.03 g, yield: 77.7%,brown oil).

The obtained methyl N-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylate (10g) was subjected to silica gel column chromatography (eluate:hexane/ethyl acetate=10/1) to give methylN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (4.8 g) and methylN-[(S)-methylbenzyl]azetidine-2-(R)-carboxylate (4.68 g).

Methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate: ¹ H-NMR(CDCl₃),δ: 7.37-7.20 (m, 5H); 3.76 (t, J=8.4 Hz, 1H); 3.75 (s, 3H); 3.45 (q,J=6.6 Hz, 1H); 3.11 (td, J=7.6 Hz, J'=2.6 Hz,1H); 2.80 (m, 1H);2.33-2.12 (m, 2H); 1.22 (d, J=6.6 Hz, 3H).

Methyl N-[(S)-methylbenzyl]azetidine-2-(R)-carboxylate: ¹ H-NMR(CDCl₃),δ: 7.37-7.20 (m, 5H); 3.61 (m, 2H); 3.36 (q, J=6.6 Hz, 1H); 3.33 (s,3H); 3.01 (m, 1H); 2.35-2.10 (m, 2H); 1.29 (d, J=6.5 Hz, 3H).

Example 2

Into a solution of methyl (RS)-2,4-dibromobutyrate (48.53 g) dissolvedin acetonitrile (400 ml) was added dropwise (R)-methylbenzylamine (67.87g) at 50° C. and the mixture was stirred at the same temperature for 3.5hours. The mixture was concentrated under reduced pressure. The obtainedresidue was mixed with toluene (200 ml) and concentrated again underreduced pressure to remove acetonitrile. The obtained residue wascombined with hexane (500 ml) and the mixture was stirred for 6.5 hours.Precipitated solid substance was filtered off to give a filtrate and thesolid substance.

The solid substance obtained above was dissolved in water (200 ml) andthe liberated organic layer was separated to give the organic layer andan aqueous layer. The aqueous layer was extracted twice with toluene (50ml) and the obtained organic layers were combined and further with theliberated organic layer.

The organic layer was further combined with the filtrate describedabove, the solvent was evaporated and the obtained residue was dissolvedin toluene and washed with water. The toluene layer was analyzed byGC-IS to reveal that the layer contained 32.1 g of methylN-[(R)-methylbenzyl]azetidine-2-(RS)-carboxylate. Yield: 78.3%.

Example 3

Into a solution of methyl (RS)-2,4-dibromobutyrate (37.49 g) dissolvedin acetonitrile (650 ml) was added dropwise a solution of(S)-methylbenzylamine (94.86 g) in acetonitrile (100 ml) at 60° C. over5.5 hours. The mixture was left to stand at room temperature for 16hours and concentrated under reduced pressure. The obtained residue wasmixed with toluene (200 ml) and concentrated again under reducedpressure to remove acetonitrile. The obtained residue was combined withether (600 ml) and hexane (200 ml) and the mixture was stirred at roomtemperature for 24 hours. Precipitated solid substance was filtered offand the filtrate was concentrated. The obtained residue was mixed withtoluene (80 ml) and extracted with 12% hydrochloric acid (100 ml). Tothe obtained aqueous layer was added 9% aqueous sodium hydrogencarbonate solution (110 ml) and extracted with toluene to form aqueousand organic layers. The aqueous layer had a pH of 4.5. The obtainedorganic layer was washed with water and the solvent was evaporated toleave a residue (20.96 g), which was distilled under reduced pressure togive methyl N-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylate [13.8 g,pale yellow oil, yield: 43.4%, b.p. 103.5-106° C. (0.2 mmHg)].

Analysis of this product by gas chromatography revealed that the ratioof methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate and methylN-[(S)-methylbenzyl]azetidine-2-(R)-carboxylate was 51/49.

To the aqueous layer of pH 4.5 obtained above was added 9% aqueoussodium hydrogen carbonate solution (50 ml) and extracted with toluene(50 ml) and then further amount of toluene (100 ml). Combined organiclayer was washed with water and concentrated to give methylN-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylate (2.56 g).

Analysis of this product by gas chromatography revealed that the ratioof methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate and methylN-[(S)-methylbenzyl]azetidine-2-(R)-carboxylate was 85/15.

Example 4

Methyl N-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylate (2.46 g)obtained in a manner similar to that in Example 1 was added to 5.6%aqueous barium hydroxide solution (34.7 g) and the mixture was stirredwithin a range of temperature of 94-98° C. for 2 hours. Then, themixture was washed twice with toluene (20 ml), once with ether (20 ml)and gaseous carbon dioxide was bubbled into the mixture at roomtemperature to precipitate barium carbonate. After stirring the mixtureat 96° C. for 30 minute, barium carbonate was removed by filtration andthe filtrate was concentrated to giveN-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylic acid, which was furthersubjected to silica gel column chromatography (eluate:chloroform/methanol=5/1-2/1) to giveN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid (0.75 g, yield:32.5%) and N-[(S)-methylbenzyl]azetidine-2-(R)-carboxylic acid (0.86 g,yield: 37.3%).

N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid: ¹ H-NMR(CDCl₃), δ:7.53-7.36 (m, 5H); 6.28 (brs, 2H); 4.40 (t, J=9.4 Hz, 1H); 4.23 (q,J=6.9 Hz, 1H); 3.88 (td, J=9.2 Hz, J'=4.0 Hz, 1H); 3.34 (q, J=9.2 Hz,1H); 2.66 (m, 1H); 2.43 (m, 1H); 1.70 (d, J=6.9 Hz, 3H).

N-[(S)-methylbenzyl]azetidine-2-(R)-carboxylic acid: ¹ H-NMR(CDCl₃), δ:7.46-7.27 (m, 5H); 5.15 (brs, 2H); 4.37 (t, J=8.7 Hz, 1H); 4.16 (m, 2H);3.54 (m, 1H); 2.41 (m, 2H); 1.7 (d, J=6.6 Hz, 3H).

Example 5

N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid (11.11 g) obtainedin a manner similar to that in Example 4 and a catalyst (palladiumhydroxide on carbon, content of palladium hydroxide: 10%) were added toa mixed solvent of ethanol (25 g) and water (25 g) and the mixture wasstirred in a hydrogen atmosphere at 27° C. for 1 hour, heated to 40° C.and stirred further at the same temperature for 10 hours. After removingthe catalyst by filtration, the filtrate was concentrated to give(S)-azetidinecarboxylic acid (5.22 g, yield: 99%, colorless crystals in100% e.e. The value of e.e. was determined by high performance liquidchromatography analysis using a chiral column.

Example 6

Methyl N-[(S)-methylbenzyl]azetidine-2-carboxylate (0.27 g, the ratio:2S isomer/2R isomer=52/48) and L-tartaric acid (0.15 g) were dissolvedin methanol (6 ml) at room temperature. Then, the mixture wasconcentrated to give tartaric acid salt of methylN-[(S)-methylbenzyl]azetidine-2-carboxylate, which was recrystallizedfrom a mixed solvent of methyl tert-butyl ether (6 ml) and methanol (2ml) to give crystals of tartaric acid salt of methylN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (0.12 g, colorlesscrystals, yield: 28%).

¹ H-NMR (DMSO), δ: 7.29 (m, 5H); 4.39 (s, 2H); 3.79 (t, J=8.3 Hz, 1H);3.70 (s, 3H); 3.47 (q, J=6.3 Hz, 1H); 3.00 (q, J=5.9 Hz, 1H); 2.77 (q,J=7.6 Hz, 1H); 2.18 (m, 2H); 1.15 (d, J=6.3 Hz, 3H).

The crystals were dissolved in a saturated aqueous sodium hydrogencarbonate solution, which was extracted with toluene. Analysis of theextract by GC revealed that the product had 99.7% d.e.

Example 7

A solution of methyl N-[(S)-methylbenzyl]azetidine-2-carboxylate (29.91g, the ratio: 2S isomer/2R isomer=52/48) in methyl tert-butyl ether wasadded dropwise to a solution of L-tartaric acid (16.55 g) in methanol(20.26 g) under reflux. Further, 21.43 g of methanol was added and theobtained homogeneous solution was cooled to 29° C. A small amount of thecrystals obtained in Example 6 was fed as seed crystals to initiatecrystallization. Then, after cooled to 5° C., crystals were collected byfiltration, washed with methyl tert-butyl ether and dried in vacuo togive tartaric acid salt of methylN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (25.36 g, yield: 48%,91% d.e.).

Example 8

Tartaric acid salt of methylN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (25.13 g) obtained inExample 7 was dissolved in methanol (126.24 g) under ref lux and a partof methanol (79.3 g) was distilled off. Then, 70 g of methyl tert-butylether was added dropwise and the mixture was filtered at roomtemperature to give crystals. The obtained crystals were washed withmethyl tert-butyl ether and dried in vacuo to give tartaric acid salt ofmethyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (20.87 a, yield:84%, 100% d.e.).

Example 9

The procedure in Example 7 was repeated in 1/5 scale except that toluenewas used in place of methyl tert-butyl ether to give tartaric acid saltof methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (4.64 g,yield: 45%, 96% d.e.).

Example 10

The procedure in Example 6 was repeated except that 0.12 g of fumaricacid was used in place of L-tartaric acid to give fumaric acid salt ofmethyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (colorlesscrystals, 0.04 g, yield: 12%, 98.1% d.e.).

Example 11

Into a solution of methyl (RS)-2,4-dibromobutyrate (91.0 g) dissolved intoluene (77 g) was added dropwise (RS)-methylbenzylamine (45.3 g) at 75°C. over 2 hours. The mixture was left to stand at 90° C. for 12 hours.Water (135 g) was added to the mixture and separated at 70° C., and theobtained organic layer was washed with water (50 g), 1% hydrochloricacid (40 g) and water (50 g). A sample of the obtained organic layer(185 g) was subjected to GC-IS analysis, which revealed yield of 76.1%and diastereomeric ratio of 51:49.

Example 12

200 g of 49.2% methyl N-[(RS)-methylbenzyl]azetidine-2-(RS)-carboxylatesolution in toluene was added dropwise to a solution of L-tartaric acid(6.84 g) in methanol (10.26 g) at 60° C. 0.005 g of tartaric acid saltof methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate was added asseed crystals to the mixture and was maintained at the temperature for0.5 hour. To the resulting slurry was added 30 g of 50% methylN-[(RS)-methylbenzyl]azetidine-2-(RS)-carboxylate in toluene solutionwas added dropwise at 60° C. over 1 hour. The slurry was cooled to 0° C.and crystals were collected by filtration. The obtained crystals werewashed with cold methanol and dried iq vacuo to give L-tartaric acidsalt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (16.5 g,yield: 15.7%, 99.7% d.e.). The obtained crystals were treated in thefollowing Example 14. 15 or 16 to yield (S)-azetidine-2-carboxylic acid.(>99% e.e).

Example 13

The reaction was conducted in a similar manner as conducted in Example12 except that methyl N-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylatewas used in place of N-[(RS)-methylbenzyl]azetidine-2-(RS)-carboxylateand in a 5.5 times scale to give L-tartaric acid salt of methylN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (101.8 g, yield: 44%,99.8% d.e.).

Example 14

20% aqueous sodium carbonate (623.2 g) was added dropwise to a mixtureof L-tartaric acid salt of methylN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (425.5 g), water (425.5g) and toluene (105 g). The reaction mixture was separated, and aqueouslayer was extracted with toluene (105 g). The combined organic layer waswashed twice with water (243 g×2), and concentrated under reducedpresssure to give methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate(249.2 g; Yield 98%).

Example 15

To a mixture of methyl N-[(S)-methylbenzyl]azetidine-2-(s)-carboxylate(161.6 g) and water (323 g) was added 2-ethylhexanoic acid (116.9 g) andresulting mixture was stirred at 60° C. for about 12 hours. Heptane (161g) was added to the reaction mixture and separated. The organic layerwas extracted with water (80 g). Combined water layer was washed withheptane (161.6 g×3) to give aqueousN-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid solution (606.2 g).Yield 94%.

Example 16

A mixture of an aqueous N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylicacid solution (74.21 g, net: 23.7 g), which had been obtained in asimilar manner as described in Example 15, and 10% palladium hydroxideon carbon (dry weight:2.08 g) was stirred under hydrogen atmosphere at50° C. for 21 hours. Acetic acid (0.76 g) was added to the reactionmixture, kept at the same temperature for 1 hour, and filtered to removethe catalyst. Separated water layer was concentrated under reducedpressure to give a residue, which was dried under reduced pressure togive a white solid of (S)-azetidine-2-carboxylic acid (12.08 g; >99%e.e). Yield 96%.

What is claimed is:
 1. An optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (2): ##STR14## wherein R¹ is an alkyl group, R² is a phenylgroup or an alkyl group which may be substituted with a phenyl group,Xis a phenyl group which may be substituted with at least one groupselected from a halogen atom, hydroxyl group, an alkyl group and analkoxy group and a and b independently designate asymmetric carbonatoms.
 2. A dicarboxylic acid salt of optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester represented by theformula (7): ##STR15## wherein R¹ is an alkyl group having 1 to 6 carbonatoms, R² is an aryl group or a saturated hydrocarbon group which may besubstituted with an aryl group,X is a phenyl group which may besubstituted with at least one group selected from a halogen atom,hydroxyl group, an alkyl group having 1 to 6 carbon atoms and an alkoxygroup having 1 to 6 carbon atoms, a and b independently designateasymmetric carbon atoms and B is a single bond; a phenylene group; astraight or branched chain alkylene group which may be substituted witha phenyl group, a hydroxy group which may be protected or a halogenatom; a cyclic alkylene group which may be substituted with a hydroxygroup which may be protected, a halogen atom or a phenyl group; or astraight or branched chain alkenylene group which may be substitutedwith a phenyl group.
 3. An N-(alkylbenzyl)azetidine-2-carboxylic acidester represented by the formula (2)': ##STR16## wherein R¹ is an alkylgroup, R² is a phenyl or an alkyl group which may be substituted with aphenyl group,X is a phenyl group which may be substituted with at leastone group selected from a halogen atom, hydroxyl group, an alkyl groupand an alkoxy group, and a independently designates an asymmetric carbonatom.
 4. An adduct of the formula (6): ##STR17## wherein R¹ is an alkylgroup having 1 to 6 carbon atoms, R² is an aryl group or a saturatedhydrocarbon group which may be substituted with an aryl group,X is aphenyl group which may be substituted with at least one group selectedfrom a halogen atom, hydroxyl group, an alkyl group having 1 to 6 carbonatoms and an alkoxy group having 1 to 6 carbon atoms and a independentlydesignates an asymmetric carbon atom, B is a single bond; a phenylenegroup; a straight or branched chain alkylene group which may besubstituted with a phenyl group, a hydroxy group which may be protectedor a halogen atom; a cyclic alkylene group which may be substituted witha hydroxy group which may be protected, a halogen atom or a phenylgroup; or a straight or branched chain alkenylene group which may besubstituted with a phenyl group.
 5. The optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 1, wherein thealkyl group is a member selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl and tert-butyl.
 6. The optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 1, wherein thealkoxy group is methoxy or ethoxy.
 7. The optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 5, wherein thealkoxy group is methoxy or ethoxy.
 8. The dicarboxylic acid salt ofoptically active N-(alkylbenzyl)azetidine-2-carboxylic acid ester ofclaim 2, wherein the alkyl group is a member selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. 9.The dicarboxylic acid salt of optically activeN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 2, wherein thealkoxy group is methoxy or ethoxy.
 10. The dicarboxylic acid salt ofoptically active N-(alkylbenzyl)azetidine-2-carboxylic acid ester ofclaim 8, wherein the alkoxy group is methoxy or ethoxy.
 11. TheN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 3, wherein thealkyl group is a member selected from the group consisting of methyl,ethyl, propyl, isopropyl, butyl and tert-butyl.
 12. TheN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 3, wherein thealkoxy group is methoxy or ethoxy.
 13. TheN-(alkylbenzyl)azetidine-2-carboxylic acid ester of claim 11, whereinthe alkoxy group is methoxy or ethoxy.
 14. The adduct of claim 4,wherein the alkyl group is a member selected from the group consistingof methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
 15. Theadduct of claim 4, wherein the alkoxy group is methoxy or ethoxy. 16.The adduct of claim 14, wherein the alkoxy group is methoxy or ethoxy.